The causes of the variability in clinical expression of sickle cell anemia (SCA) (SS) are poorly understood. Recently, we have shown that DNA polymorphisms flanking the beta(s)-gene and the number of alpha- globin genes define genotypic subsets of SCA are associated with strikingly different risks of overall vasocclusive disease severity as well as individual vasocclusive complications. Specific polymorphisms of the beta(s)-gene cluster are associated with differential levels of increased fetal hemoglobin and (G)gamma Hb F production which may in part explain the variability in the risk of sickle cell induced end organ damage. In the present proposal, we seek to build upon and extend these observations. We hypothesize that the polymorphisms of the beta(s)-gene cluster are consistently associated with different degrees of abnormality of red cell and other phenotypic parameters which contribute to vascular occlusion and, furthermore, that the combination of genotypic and phenotypic analysis will better predict clinical disease severity. The project has two main goals. First, we wish to determine whether the observed differences in vasocclusive disease severity characteristic of different genotypic subsets of SCA can be explained by differences in RBC and other phenotypic abnormalities thought to the relevant to the pathogenesis of vascular occlusion. Second, we wish to determine whether phenotypic analysis improves the predictive value of genotypic analysis for the risk of vasocclusive disease in SCA. These investigations should shed additional light on the pathogenesis of vascular occlusion in SCA. These investigations should shed additional light on the pathogenesis of vascular occlusion in SCA, as well as improve the prediction of clinical disease severity in the individual subject with SCA which could have important implications for treatment stratification.